Efficacy and Safety of Trametinib Monotherapy or in Combination with Dabrafenib in Pediatric BRAF V600-Mutant Low-Grade Glioma

Eric Bouffet, Birgit Geoerger, Christopher Moertel, James A. Whitlock, Isabelle Aerts, Darren Hargrave, Lisa Osterloh, Eugene Tan, Jeea Choi, Mark Russo, Elizabeth Fox

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


PURPOSEBRAF V600 mutations occur in many childhood cancers, including approximately 20% of low-grade gliomas (LGGs). Here, we describe a phase I/II study establishing pediatric dosing and pharmacokinetics of trametinib with or without dabrafenib, as well as efficacy and safety in a disease-specific cohort with BRAF V600-mutant LGG; other cohorts will be reported elsewhere.METHODSThis is a four-part, phase I/II study (ClinicalTrials.gov identifier: NCT02124772) in patients age < 18 years with relapsed/refractory malignancies: trametinib monotherapy dose finding (part A) and disease-specific expansion (part B), and dabrafenib + trametinib dose finding (part C) and disease-specific expansion (part D). The primary objective assessed in all patients in parts A and C was to determine pediatric dosing on the basis of steady-state pharmacokinetics. Disease-specific efficacy and safety (across parts A-D) were secondary objectives.RESULTSOverall, 139 patients received trametinib (n = 91) or dabrafenib + trametinib (n = 48). Trametinib dose-limiting toxicities in > 1 patient (part A) included mucosal inflammation (n = 3) and hyponatremia (n = 2). There were no dose-limiting toxicities with combination therapy (part C). The recommended phase II dose of trametinib, with or without dabrafenib, was 0.032 mg/kg once daily for patients age < 6 years and 0.025 mg/kg once daily for patients age ≥ 6 years; dabrafenib dosing in the combination was as previously identified for monotherapy. In 49 patients with BRAF V600-mutant glioma (LGG, n = 47) across all four study parts, independently assessed objective response rates were 15% (95% CI, 1.9 to 45.4) for monotherapy (n = 13) and 25% (95% CI, 12.1 to 42.2) for combination (n = 36). Adverse event-related treatment discontinuations were more common with monotherapy (54% v 22%).CONCLUSIONThe trial design provided efficient evaluation of pediatric dosing, safety, and efficacy of single-agent and combination targeted therapy. Age-based and weight-based dosing of trametinib with or without dabrafenib achieved target concentrations with manageable safety and demonstrated clinical efficacy and tolerability in BRAF V600-mutant LGG.

Original languageEnglish (US)
Pages (from-to)664-674
Number of pages11
JournalJournal of Clinical Oncology
Issue number3
StatePublished - Jan 20 2023

Bibliographical note

Funding Information:
The authors thank the patients who participated in the trial and their families. The authors also thank the physicians, nurses, research coordinators, and other staff at each site who assisted with the study. We also thank Karen Wright, Kenneth Cohen, and Lindsay Kilburn for enrollment of patients onto the trial and Neha Pakhle (Novartis Pharmaceuticals Corporation) for statistical analysis, guidance, and critical review of the report. Editorial assistance was provided by Amy Ghiretti, PhD; Allison Lytle, PhD; and Laura Hilditch, PhD (Articulate Science LLC), and was funded by Novartis Pharmaceuticals Corporation.

Publisher Copyright:
© American Society of Clinical Oncology.


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